Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and the biggest single gene contributor to autism, with a frequency of 1 in 4000 males and 1 in 6000 females. Almost all cases of FXS are caused by an expansion of the CGG trinucleotide repeat in the FMR1 (fragile X mental retardation 1) gene, which codes for the RNA-binding protein FMRP (Fragile X mental retardation protein). In these cases, CGG is abnormally repeated from 200 to more than 1,000 times, which makes this region of the gene unstable and little or no FMRP is produced. The loss or shortage of FMRP disrupts normal neuronal function, causing severe learning problems, intellectual disability, and the other features of FXS. The hallmark neurobehavioral symptoms of FXS include hyperactivity, defects in sensory integration, communication difficulties, poor motor coordination, social anxiety and restricted repetitive and stereotyped patterns of behavior. Among the hallmark phenotypes reported in individuals with FXS are deficits in attentional function, inhibitory control, and cognitive flexibility. FXS is also a well-characterized form of autism spectrum disorder. About one-third of males with an FMR1 gene mutation and the characteristic signs of fragile X syndrome also have features of autism spectrum disorder that affect communication and social interaction.
Several neurotransmitters and signaling pathways have been found to mediate FMRP function, including group I metabotropic glutamate receptor type 5 (mGluR5), N-methyl-D-aspartate receptor subunits, GABAA receptor, mTOR, TSC-2 and GSK3β. These discoveries led to the development of pharmaceuticals for FXS, including lithium (GSK3β attenuation), GABAA agonists, mGluR5 antagonists, including fenobam, which have been shown to reverse multiple phenotypes in FXS such as audiogenic seizures, open field hyperactivity, and dendritic spine morphology.
FMRP is highly expressed in neurons, and studies show that FMRP regulates neurotransmitters and neuronal signaling molecules. Although many targets for treating FXS have emerged, the clinical failures of two recent large mGluR5-antagonist programs in FXS have forced drug developers to rethink target selection for neurodevelopmental indications. Thus, there is a need to develop new, improved and effective methods to treat fragile X syndrome, autism, and mental retardation.